1. Modafinil
Modafinil has been described as presenting a “neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialization of the effects of apomorphine and amphetamine” (U.S. Pat. No. 4,177,290; hereinafter “the '290 patent,” which is incorporated herein by reference). A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys (Duteil et al., Eur. J. Pharmacol. 180:49 (1990)). The neuropsychopharmacological profile of modafinil has been distinguished from that of amphetamines (Saletu et al., Int. J. Clin. Pharm. Res. 9:183 (1989)). Modafinil is thought to modulate the central postsynaptic alpha1-adrenergic receptor, without participation of the dopaminergic system (Duteil et al., supra). Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuro-Psych. Biol. Psych. 12:695 (1988)).
Modafinil has been shown to be effective in treating narcolepsy, sleepiness, excessive sleepiness (e.g., sleepiness associated with disorders of sleep and wakefulness), excessive daytime sleepiness associated with narcolepsy, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, ADHD, Alzheimer's disorder, sleep apnea, obstructive sleep apnea, depression, and ischemia.
Narcolepsy is a chronic disorder characterized by intermittent sleep attacks, persistent, excessive daytime sleepiness and abnormal rapid eye movement (“REM”) sleep manifestations, such as sleep-onset REM periods, cataplexy, sleep paralysis and hypnagogic hallucinations, or both (Assoc. of Sleep Disorders Centers, Sleep 2:1 (1979)). Most patients with narcolepsy also have disrupted nocturnal sleep (Montplaisir, in Guilleminault et al. eds., Narcolepsy, Spectrum Pub., New York, pp. 43-56). Pathological somnolence, whether due to narcolepsy or other causes, is disabling and potentially dangerous. Causes of pathological somnolence, other than narcolepsy, include chronic sleep loss (Carskadon et al., Sleep, 5:S73 (1982); Carskadon et al., Psychophysiology, 18:107 (1981)); sleep apnea (Kryger et al., Principles and Practice of Sleep Medicine, W. B. Saunders Co., Philadelphia, Pa. (1989)); and other sleep disorders (International Classification of Sleep Disorders: Diagnostic and Coding Manual, American Sleep Disorder Association, Rochester, Minn. (1990)). Whether due to narcolepsy or other causes, pathological somnolence produces episodes of unintended sleep, reduced attention, and performance errors. Consequently, it is linked to a variety of transportation and industrial accidents (Mitler et al., Sleep 11:100 (1988)). A therapeutic agent that reduces or eliminates pathological somnolence would have important implications not only for individual patients, but also for public health and safety.
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745 discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e., (−) benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855). European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
U.S. Pat. No. RE37,516 discloses pharmaceutical compositions having a defined particle size, and in particular compositions wherein 95% of the cumulative total of an effective amount of modafinil particles in the composition have a diameter less than about 200 microns.
Particles of modafinil can be formed via precipitation, granulation and milling or by extrusion/spheronization.
2. Alternative Dosage Forms: Generally
Control of delivery can be important when traditional oral or injectable formulations cannot be used. The features of controlled release may include, but are not limited to:                a. slow release of water-soluble drugs;        b. fast release of low-solubility drugs;        c. delivery to specific sites;        d. delivery of two or more actives in the same formulation; and        e. systems based on carriers that can dissolve or degrade and be readily eliminated.        
Controlled drug delivery can also provide the following advantages:                a. eliminate over or underdosing;        b. maintain drug levels in a desired range;        c. reduce the need for repetitive dosing;        d. increased patient compliance; and        e. assist in the redirection or prevention of side effects.        
Oral dosage forms are known which provide a zero order or first order release in which the drug is released at a substantially steady rate of release per unit of time. These dosage forms are satisfactory for the administration of pharmaceutical dosage forms of many drugs. Such dosage forms provide for an increase of blood levels of a drug that peaks and then begins to fall as the drug is metabolized or otherwise excreted.
However, in certain circumstances, more constant blood levels of a drug or multiple peaks are desirable. Such dosage forms which can provide such an effect are generally referred to as “Extended Release Dosage Forms.” As used herein, extended release dosage forms that provide generally constant blood levels of a drug over time are referred to as “sustained release forms,” and dosage forms that provide distinct blood level peaks of a drug over time are referred to as “pulsatile release forms.” Both of these forms are described generally below.
A. Sustained Release Forms
A sustained release drug formulation is capable of providing immediate release of a drug, yet prolong the release of the drug such that the blood levels of the drug are maintained within a relatively narrow range over a period of time.
Sustained release drug formulations can be conventionally produced as compressed tablets, e.g., by hydrogel tablet technology. Among other alternatives, it is conventional in the drug industry to prepare encapsulated drug formulations which provide sustained release properties. In this situation, the sustained release capsule dosage forms may be formulated by mixing the drug with one or more binding agents to form a uniform mixture which is then moistened with water or a solvent such as ethanol to form an extrudable plastic mass from which small diameter, typically 1 mm, cylinders of drug/matrix are extruded, broken into appropriate lengths and transformed into spheroids using standard spheronization equipment. The spheroids, after drying, may then be film-coated to retard dissolution. The film-coated spheroids may then be placed in pharmaceutically acceptable capsules, such as starch or gelatin capsules, in the quantity needed to obtain the desired therapeutic effect. Spheroids releasing the drug at different rates may be combined in a capsule to obtain desired release rates and blood levels. U.S. Pat. No. 4,138,475 discloses an extended release pharmaceutical composition consisting of a hard gelatin capsule filled with film-coated spheroids comprised of propanol in admixture with microcrystalline cellulose wherein the film coating is composed of ethyl cellulose, optionally, with hydroxypropylmethylcellulose and/or a plasticizer.
B. Pulsatile Release Forms
As described above, an oral dosage form which provides a zero order or first order release in which a drug is released at a substantially steady rate of release per unit of time can be satisfactory for the administration of a drug in certain situations, depending on the needs of the subject.
However, in some instances, a pulsatile release form can be used to provide two or more dosings of a drug, typically with a predetermined period of time between each dose or at specific sites along the gastrointestinal tract, without the need for two or more oral administrations. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms.
The term “pulsatile release forms” (hereafter sometimes referred to as “pulsatile forms”) is synonymous with the term “modulated delivery systems” and according to Peppas (N. A. Peppas, Preface in R. Gumy; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, 1 Ed., page 5-5, Wiss. Verlagsges., Stuttgart 1993) designates a delivery system for medication which is capable of delivering the contained medical agent in prescribed intervals.
Until now, the preferred field of application of pulsatile forms of medication were illnesses such as ischemic heart disease, asthma, arthritis, avoiding developing a tolerance to nitrates, antibiotics and steroidal contraceptives, where absorption windows exist, HIV/AIDS, and states of pain (H. E. Junginger, Oral Applications of Pulsatile Drug Delivery in R. Gumy; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, Ed. 1, pages 113-134, Wiss. Verlagsges., Stuttgart 1993). These illnesses or states of pain are subjected to time variations such that they can be treated best with forms of medication which are adapted with the intermittent (pulsatile) release of the medical agents to the occurrence of episodes of the illness or of attacks of the pain. Clearly, in such cases, a “time-controlled” pulsatile drug delivery system may be more advantageous. There are also instances in which a “position-controlled” drug delivery system (e.g. treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious.
Typical pulsatile forms of medication deliver the contained medical agent in one step (one pulse system), two steps (bimodal, double pulse system). In addition, however, more complicated systems and mixed systems have been described, which can possibly deliver the medical substances in several steps.
Junginger (H. E. Junginger, Oral Applications of Pulsatile Drug Delivery in R. Gumy; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, Ed. 1., pages 113-134, Wiss. Verlagsges., Stuttgart 1993) gives examples for pulsatile forms of medication and recites in particular: coated tablets, pellets or microballs, osmotic systems, special capsules, time-controlled explosion systems, and special layer tablets.
3. Dosings of Modafinil
Typically, modafinil is administered in 100 mg and/or 200 mg doses once or twice daily to a person having a condition that is responsive to treatment by modafinil. Preferably, a single dose having an effective amount of modafinil is administered to the person upon waking. However, in some instances a second dose, also having an effective amount of modafinil, can be administered about six to twelve hours after the first dose in order to increase blood levels of modafinil to levels sufficient to continue to treat the condition or conditions that are responsive to modafinil.
With traditional dosings, it is desirous for blood levels of a drug to remain between a maximum blood level which may represent a toxic level and a minimum value below which the drug is no longer effective. However, maintenance of blood levels can be difficult. For example, traditional dosage forms can provide an erratic blood concentration profile. After administration of a first dose, blood levels can increase and exceed the maximum desired level, then drop off to levels below the minimum effective level before a second or subsequent dose is administered. The same cycle can be undesirably repeated with subsequent dosings of modafinil.